Lesperienza di Verona Massimiliano Bonifacio only considering Acute - - PowerPoint PPT Presentation

L’esperienza di Verona Massimiliano Bonifacio

• nly considering Acute Lymphoblastic Leukemia…
• Case reports, biological studies, others
• Original reports of clinical trials

10 11 98

• Reviews and commentaries

A clinical case

• D. (d.o.b. May 1984) was diagnosed with Philadelphia-neg, standard risk,

TEL-AML1+, B-precursor common ALL in April 2009.

• She was treated with a pediatric-like regimen (GIMEMA/AIEOP LAL1308

protocol) obtaining MRD-negative CR after induction.

• She remained in complete MRD response until maintenance therapy

completion and she went off-therapy in April 2011.

• In November 2013, during a routine bone marrow check, a MRD relapse was

documented (both by flow cytometry and molecular analysis) with rapidly raising values (from 1x10-4 to 5x10-2)

• She was enrolled in the BLAST trial, obtaining complete MRD response after

the 1st cycle. It was decided to not proceed to allogeneic HSCT. She received 3 consolidation cycles of blinatumomab and ended treatment on May 2014.

Bonifacio M, Tanasi I, et al. manuscript in preparation

A clinical case

• In December 2014 (during the regular 6-month follow-up visit after

blinatumomab end) she reported the suspicion of an unplanned pregnancy, which was confirmed by lab tests.

• On 14th August 2015 she delivered a healthy male baby.
• In December 2015 a second MRD relapse was documented (both by flow

cytometry and molecular analysis, 2x10-3) and confirmed 1 month apart with slightly rising levels (3x10-3).

• She was treated with another cycle of blinatumomab between February and

March 2016, obtaining a MRD response (positive below LLOQ).

• She underwent allogeneic HSCT from sibling donor on 19 Apr 2016

(Endoxan – TBI as conditioning regimen).

Bonifacio M, Tanasi I, et al. manuscript in preparation

0,00001 ¡ 0,0001 ¡ 0,001 ¡ 0,01 ¡ 0,1 ¡ 1 ¡

A clinical case

MRD level 10-2 10-3 10-4 10-5 1 10-1

blinatumomab

pregnancy

blinatumomab ALLOSCT

Blinatumomab in MRD+ B-ALL Inclusion criteria

Pilot experience (German multicenter MT103-202 trial – n=21)

• Patients with B-precursor ALL in first hematological CR with molecular failure or

molecular relapse

• MRD >10-4

Confirmatory study (International multicenter MT103-203 trial – n=116)

• Patients with B-precursor ALL in hematological CR with molecular failure or

molecular relapse, including patients in 2nd or later remission

• MRD, defined as a level of ≥ 10-3 in an assay with a minimum sensitivity of 10-4

BLAST multicenter MRD study Causes of screening failure

BLAST multicenter MRD study Complete MRD response after cycle 1

Gokbuget N et al. ASH 2014

Multicenter MT103-211 study in rel/ref B-ALL Subgroup analyses of CR/CRh

Topp et al. Lancet Oncol 2015;16:57-66.

All responders Sex Female Male Age 18 to <35 35 to <55 55 to <65 ≥65 Prior Salvage 1 2 ≥3 Primary refractory Yes Prior HSCT Yes Bone marrow blasts <50% ≥50%

20 40 60 80 100

189 43 46 41 43 44 36 46 50 34 36 47 38 43 45 42 29 73 70 119 16 173 64 125 90 46 28 25 38 77 42 32 59 130 No No CR/CRh Rate, % 36–50 34–58 32–51 33–54 24–65 19–56 31–61 33–67 19–53 22–52 35–58 15–65 36–51 33–58 33–51 22–38 60–84 N CR/CRh % 95% CI

BLAST multicenter MRD study Long-term outcome

Gokbuget N et al. ASH 2015

Median (95% CI), Months Relapse-free
 Survival* Overall
 Survival Overall (n=112) 18.9 (12.3 - 35.2) 36.5 (19.2 - NR) By MRD complete response MRD complete responders (n=88) MRD non-responders (n=24) NR (6.0 - NR) 3.6 (1.6 - 5.7) 38.9 (33.7 - NR) 10.5 (3.8 - NR) By remission status First CR (n=75) Second/third CR (n=35) 24.6 (18.7 - NR) 11.0 (6.8 - 15.4) 36.5 (20.6 - NR) 19.1 (11.9 - NR)

CR = complete remission; MRD = minimal residual disease; NR = not reached MRD response was defined as MRD < 10-4 (minimum sensitivity 10-4) *RFS censoring at HSCT or post-blinatumomab chemotherapy.

BLAST multicenter MRD study Relapse free survival

Gokbuget N et al. ASH 2015

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 15 11 7 7 5 4 3 3 3 3 1 1 85 77 68 63 60 57 34 33 24 23 15 15 8 7 3 3 3 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54

Study Month

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2: 1: Number of Subjects at Risk:

2: MRD non-responder at cycle 1 (N = 15) Median 95% CI 5.7 ( 1.6, 13.6) 1: MRD responder at cycle 1 (N = 85) Median 95% CI 23.6 ( 17.4, - )

| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | 3

Survival Probability

Complete MRD response (primary endpoint): MRD negative, no amplification in PCR (minimum sensitivity 10-4) NR = not reached. The landmark analysis by MRD response included patients with overall survival of ≥ 45 days

RFS in MRD complete responders: 58% at 18 months

Our experience in MRD+ B-ALL Patient characteristics

Patient Age Cytogenetics Molecular Previous treatments MRD Level of MRD at study entry #001 female 35y t(14;19?)(q32;q?) GIMEMA induction / 2 consolid / mainten relapse 1.8x10-2 #002 male 51y normal GIMEMA induction (res) FLAI salvage (CR MRD+) failure 3.8x10-2 #003 male 46y normal NILG induction / 1 consolid (CR MRD+) failure 2.2x10-3 #004 male 22y normal AIEOP induction (late CR) / 1 consolid (CR MRD+) failure 3x10-3 #005 male 52y normal GIMEMA induction / 2 consolid (CR MRD+) failure 1.3x10-2 #006 female 19y TEL/AML1+ AIEOP induction / consolid (standard risk) / maintenance late relapse (>3 yrs) 5x10-2 #007 male 32y normal NILG induction / reinduction (late CR) failure 6x10-2

Our experience in MRD+ B-ALL Outcome

Patient N° of cycles Complete MRD Response after C1 Status at transplant Outcome #001 female 2 Yes Hematologic relapse à chemotx à CR Death in remission (at d+77 after HSCT due to acute GVHD) #002 male 3 Yes Complete MRD response Death in remission (at d+102 after HSCT due to wasting encephalopathy of unknown origin) #003 male 2 n.v. Complete MRD response (flow cytometry) Relapse and death (after a second HSCT) #004 male 2 Yes MRD response (positive below LLOQ) Relapse – alive in CR (chemotx + blina + DLI) (+27 months after transplant) #005 male 3 Yes Complete MRD response Death in remission (at +18 months after HSCT due to rapidly fatal multifocal cerebral astrocytoma) #006 female 4 Yes MRD relapse Alive (severe pneumonia after HSCT) #007 male 3 Yes Complete MRD response Alive in CR (+7 months after transplant)

First remission (N = 60) Second or later remission (N = 25)

Cox model analyses of HSCT as time-dependent covariate for RFS First remission Second or later remission Hazard ratio: 2.26 (95% CI: 0.73, 6.97) 0.33 (95% CI: 0.11, 0.98) P 0.15 0.046

Transplant realization rate: 72% Simon-Makuch Plot of RFS (Landmark 45 days)

Study Month (Landmark Analysis Beginning at Study Day 45)

Yes: 46 (77%) No: 14 (23%) Allo SCT prior to relapse or censoring:

Probability of RFS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Allo SCT No Allo SCT

0.0 0.2 0.4 0.6 0.8 1.0

Probability of RFS

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

Allo SCT No Allo SCT

0.0 0.2 0.4 0.6 0.8 1.0 Yes: 15 (60%) No: 10 (20%) Allo SCT prior to relapse or censoring:

Gokbuget N et al. ASH 2015

BLAST multicenter MRD study Role of SCT in pts with complete MRD response

Blinatumomab and transplant: an open question

MRD complete response rate: 80%

All patients (n=20) 61% Transplanted patients (n=9) Non transplanted patients (n=11) All responses within the first cycle of treatment

Topp et al. J Clin Oncol 2011;29:2493-2498. Topp et al. Blood 2012;120:5185-5187.

First Blinatumomab Phase 2 Study in MRD-Positive ALL

Topp et al. Lancet Oncol 2015;16:57-66.

Overall survival Relapse-free survival

Median, months (95% CI) Median, months (95% CI) Probability of OS Months No censoring 5.9 (4.8–8.3) Censoring for HSCT 5.9 (4.2–6.9) Probability of RFS 18 0.0 2 4 6 8 10 12 14 16 1.0 0.8 0.6 0.4 0.2 Months No censoring 6.1 (4.2–7.5) Censoring for HSCT 5.1 (4.1–7.1) 18 0.0 2 4 6 8 10 12 14 16 1.0 0.8 0.6 0.4 0.2

Blinatumomab and transplant: an open question

in relapsed/refractory patients

Kantarjian et al. Cancer 2016 [epub]

Blinatumomab and transplant: an open question

Overall survival Relapse-free survival

in relapsed/refractory patients

Safety profile of blinatumomab

Most common clinical AE are early, transient, reversible and do not require discontinuation of treatment

• Pyrexia (60-90%)

Ÿ Tremor (29-36%)

• Headache (38-47%)

Ÿ Fatigue (24-50%) Laboratory abnormalities (lymphopenia, leukopenia, C-reactive protein increase, decrease of immunoglobulins) are common. Fatal cases of infections occurred during or after treatment with blinatumomab, mainly in rel/ref patients and before that response could be assessed or in non-responder patients. Dose-dependent CNS adverse events occurred in all clinical studies:

• Seizure, encephalopathy, ataxia, apraxia, aphasia, tremor
• Reversible, no sequelae, no pathological changes in MRI
• Main cause of treatment interruption in 31% of MRD+ and 15% of rel/ref pts
• Predictive marker identified: low B:T cell ratio in peripheral blood (B:T<1:8)

• No severe / unexpected toxicities during treatment

(absence of neurological events, systematic use of levetiracetam prophylaxis).

• Despite deep molecular responses in all patients, there are

early relapses, in patients planned for allogeneic transplantation.

• It is unknown what it the ideal compromise between wash-
• ut after blinatumomab treatment and no transplant delay.
• Infections after HSCT occur and influence outcome.

Some considerations from our experience

• How to combine blinatumomab with chemotherapy

(concurrent or sequential use)?

• Sequential combination with other novel drugs

(inotuzumab)?

• Earlier treatment with blinatumomab – before selection of

genetically unstable, resistant clones – can avoid HSCT to some patients?

• Maintenance treatment is safe? may prolongs survival?

Open questions